198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

Crystalline Polymorphism of Organic Compounds 165
control in polymorphism is briefly addressed with a view to illustrating current
strategies and their implications for the design of solids.
2
Crystal Polymorphism – Theoretical Principles and Practical Implications
2.1
Background – The Role of Polymorphism in the Production of Materials
Many of the inconsistencies encountered in product performance in the chemical,
chemical engineering, pharmaceutical, food and related industries can be
attributed to polymorphism.An important example is inconsistent behaviour of
drug substances upon dissolution which may have a direct influence on bioavailability.
This arises because different polymorphic forms of the same drug may
have solubilities which differ by an order of magnitude [24]. Inadvertent
production of the ‘wrong’ polymorph at the crystallization stage following synthesis
or at any of the intermediate processing stages can therefore result in
pharmaceutical dosage forms which are either ineffective or toxic [37, 38]. Spontaneous
polymorphic transformations mediated by solvents is common [4] and
liquid preparations of metastable drugs frequently lose their effectiveness due
to precipitation of less soluble, thermodynamically more stable polymorphs or
pseudopolymorphs. A case in point is the antiprotozoal agent metronidazole
benzoate which, when stored as an aqueous suspension below 38 °C is metastable,
leading to precipitation and growth of the insoluble monohydrate
[39, 40].
Dunitz and Bernstein [5] have recently documented several cases of “vanishing”
polymorphs. These are usually metastable forms which, despite their
thermodynamic instability, may have crystallized preferentially due to more
rapid nucleation. Such metastable forms may persist and be used for many years
before being “displaced”, when a thermodynamically more stable form is prepared.
Attempts to regenerate the original polymorph are frequently met with
failure. Specific compounds with such a history include e.g. 1,2,3,5-tetra-
O-acetyl-b-D-ribofuranose, benzocaine picrate and xylitol. This disturbing
phenomenon extends to pseudopolymorphs. A previously known monohydrate
of the antibiotic ampicillin has not been obtained since the appearance of the
trihydrate [24]. A possible explanation for this behaviour is that after minute
particles of the stable polymorph enter the environment, they eventually become
widely disseminated (“planetary seeding” [5]) and serve as nuclei promoting
crystallization of their own kind exclusively.
Manufacturing processes including crystallization scale-up, drying, heating,
compression and milling can induce polymorphic transformations [24] and it
follows that careful quality control is necessary at all stages to monitor undesirable
changes. Systematic investigation of a compound to determine whether it is
prone to polymorphism, as well as the nature of the polymorphism (enantiotropic
or monotropic) [23], is routine practice in pharmaceutical pre-formulation
studies. Identification of the different polymorphic forms of a drug substance,
determination of their chemical and physical properties, thermodynamic